Outbreaks of Mycobacterium tuberculosis MDR strains differentially induce neutrophil respiratory burst involving lipid rafts, p38 MAPK and Syk

María Mercedes Romero,Mercedes Alemán,María Del Carmen Sasiain,Lucía Barrera,Beatriz López,Viviana Ritacco,Juan Ignacio Basile

doi:10.1186/1471-2334-14-262

María Mercedes Romero, Mercedes Alemán + Show 5 more

Open Access

https://doi.org/10.1186/1471-2334-14-262

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Abstract

BackgroundNeutrophils (PMN) are the first cells to infiltrate the lung after infection, and they play a significant protective role in the elimination of pathogen, by releasing preformed oxidants and proteolytic enzymes from granules and generating ROS, thus limiting inflammation by succumbing to apoptosis. In a previous study, we found marked differences in ROS-induced apoptosis between two Mycobacterium tuberculosis (Mtb) strains, M and Ra, representative of widespread Mtb families in South America, i.e. Haarlem and Latin-American Mediterranean (LAM), being strain M able to generate further drug resistance and to disseminate aggressively.MethodsIn this study we evaluate the nature of bacteria-PMN interaction by assessing ROS production, apoptosis, lipid raft coalescence, and phagocytosis induced by Mtb strains.ResultsDectin-1 and TLR2 participate in Mtb-induced ROS generation and apoptosis in PMN involving p38 MAPK and Syk activation with the participation of a TLR2-dependent coalescence of lipid rafts. Further, ROS production occurs during the phagocytosis of non-opsonized bacteria and involves α-glucans on the capsule. In contrast, strain M lacks the ability to induce ROS because of: 1) a reduced phagocytosis and 2) a failure in coalescence of lipid raft.ConclusionsThe differences in wall composition could explain the success of some strains which stay unnoticed by the host through inhibition of apoptosis and ROS but making possible its replication inside PMN as a potential evasion mechanism. Innate immune responses elicited by Mtb strain-to-strain variations need to be considered in TB vaccine development.

Highlights

Neutrophils (PMN) are the first cells to infiltrate the lung after infection, and they play a significant protective role in the elimination of pathogen, by releasing preformed oxidants and proteolytic enzymes from granules and generating reactive oxygen species (ROS), limiting inflammation by succumbing to apoptosis
Given that TLR2 has been shown to be involved in apoptosis induced by H37Rv in Polymorphonuclear cells (PMN) [25] and in turn it cooperates with dectin-1 in the recognition of non virulent mycobacteria such as M. smegmatis in MØ [26], we studied the implication of TLR2 and dectin-1 in the generation of ROS induced by clinical isolates
We found that Ra-induced ROS production was significantly reduced by blocking dectin-1 with specific antibodies or with laminarin, a soluble β-glucan

Summary

Introduction

Neutrophils (PMN) are the first cells to infiltrate the lung after infection, and they play a significant protective role in the elimination of pathogen, by releasing preformed oxidants and proteolytic enzymes from granules and generating ROS, limiting inflammation by succumbing to apoptosis. We found marked differences in ROS-induced apoptosis between two Mycobacterium tuberculosis (Mtb) strains, M and Ra, representative of widespread Mtb families in South America, i.e. Haarlem and Latin-American Mediterranean (LAM), being strain M able to generate further drug resistance and to disseminate aggressively. Mtb capsular carbohydrates are absent in some other taxa and mediate specific interactions with the host [9]. The major carbohydrate constituents from Mtb surface are α-glucans, which represent up to 80% of the extracellular polysaccharides. These α-glucans are composed of a 4-α-DGlc-1 core branched at position 6 every five or six residues by 4-α-D-Glc-1 oligoglucosides [7,8,10]

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